The long-range objectives of this proposal are to determine the physiological effects and mechanisms of action of the neuropeptide family of prosomatostatin-derived peptides (SSs) and the functional role of endogenous somatostatins. Other major objectives are to investigate possible interactions of the SSs with other transmitter candidates and to correlate neuronal SS responsivity with immunohistochemical indices of SSergic innervation. Preliminary electrophysiological studies of the SSs suggest that the K+ conductance known as the M-current is enhanced by SS14 and SS28, leading to the suggestion that SSs may function to clamp the neuronal membrane potential at resting levels. Thus, SS may play a major role in reducing responses to excitatory amino acids (glutamate and NMDA) and therefore could be involved in certain brain phenomena such as long-term potentiation (LTP; a model of learning), hyperexcitability and excitotoxicity. The SS potentiation of cholinergic effects (seen previously) could also be significant with respect to memory precesses and also to Alzheimer's dementia. The specific aims of this proposal are therefore to: 1) characterize the physiological mechanisms of action of SS; 2) further characterize SS interactions with other transmitters; 3) seek anatomical correlates of SS responses; 4) determine if SSs, with or without ACh, alter LTP in the hippocampus; 5) determine if SSs alter low-Mg++ induced neuronal hyperexcitability. To achieve these aims, intracellular current-clamp and single electrode voltage-clamp recording of neurons in several in vitro brain slice preparations will be used, including those from the hippocampus CA1, dentate gyrus, complex of the solitary tract, and cerebral cortex. SSs, acetylcholine, GABA, glutamate, NMDA, CRF and other drugs will be applied by superfusion or locally via pipette. Pathway stimulation and/or treatment with a SS antagonist, cysteamine or antibodies to SS will be used to determine the role of endogenous SSs. Intracellular injection of Lucifer Yellow and immunohistochemical staining of SS- containing fibers will provide anatomical correlates. These studies will help to clarify the sites and mechanisms of action of the SS peptides, and perhaps lead to therapeutic use of synthetic SS peptides in clinical disease states.